Obesity and type-2 diabetes (T2D) are two epidemic problems, but partly due to limited understandings on the underlying mechanisms, currently there are inadequate interventional approaches to treat or prevent these diseases. Having appreciated that IKK/NF-?B-dependent inflammation mediates neuronal dysregulations in the brain and particularly the hypothalamus, the long-term objective of this research is to study the involved neural connections, molecular pathways, and physiological basis which can eventually lead to new strategies in treating and preventing these diseases. Preliminary studies have focused on astroglia which account for majority of brain cells, and using astroglia-specific mouse models with IKK/NF-?B activation or inhibition, it was revealed that IKK/NF-?B activation in astroglia causes neuronal inflammation leading to energy imbalance that promotes obesity development. Conversely, IKK/NF-?B inhibition in astroglia can protect neuronal functions to provide anti-obesity benefits. Hence, this project hypothesizes that astroglial IKK/NF-?B is sensitively activated by overnutrition to adversely affect neurons and cause metabolic dysregulations that underlie the development of obesity and T2D; conversely, IKK/NF-?B inhibition in astroglia help improve the micro-environment of neurons leading to improved neuronal functions and thus counteraction against these diseases. Three Specific Aims are propsoed: (1) Study the action of astroglial IKK/NF-?B in inducing neuronal inflammation; (2) Study the role of astroglial IKK/NF-?B in affecting neuronal metabolic regulation; (3) Study the disease relevance of astroglial IKK/NF-?B and its crosstalk with neurons. A combined genetic and gene delivery appraoches together with relevant neural analyses will be used to carry out these Aims. All key animal models, reagents and techniques have been established, and supportive preliminary results have been obtained. Overall, successful completion of this project will significantly clarify the brain mechanism of obesity and T2D, and enlighten the development of interventional strategies against these diseases.